title: MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas.
abstract: The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r=0.465, P<0.0001), increased copy number gain (r=0.393, P=0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324-2.395; P<0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227-2.541; P=0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r=0.274, P=0.002), copy number gain or survival (P>0.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors.
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sang Y
authors.initials: SY
authors.lastname: Ha
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.forename: So Y
authors.initials: SY
authors.lastname: Kang
authors.forename: In-Gu
authors.initials: IG
authors.lastname: Do
authors.forename: Soomin
authors.initials: S
authors.lastname: Ahn
authors.forename: Joon O
authors.initials: JO
authors.lastname: Park
authors.forename: Won K
authors.initials: WK
authors.lastname: Kang
authors.forename: Min-Gew
authors.initials: MG
authors.lastname: Choi
authors.forename: Tae S
authors.initials: TS
authors.lastname: Sohn
authors.forename: Jae M
authors.initials: JM
authors.lastname: Bae
authors.forename: Sung
authors.initials: S
authors.lastname: Kim
authors.forename: Minji
authors.initials: M
authors.lastname: Kim
authors.forename: Seonwoo
authors.initials: S
authors.lastname: Kim
authors.forename: Cheol K
authors.initials: CK
authors.lastname: Park
authors.forename: Sai-Hong
authors.initials: SH
authors.lastname: Ignatius Ou
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000368:Aged; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor / Q000032:analysis*; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met